TMEM63 proteins function as monomeric high-threshold mechanosensitive ion channels.
IL2
OSCA
TM6
TMC
TMEM16
TMEM63
high-threshold
ion channel
mechanosensitive
oligomerization
Journal
Neuron
ISSN: 1097-4199
Titre abrégé: Neuron
Pays: United States
ID NLM: 8809320
Informations de publication
Date de publication:
18 10 2023
18 10 2023
Historique:
received:
17
10
2022
revised:
12
05
2023
accepted:
08
07
2023
pmc-release:
18
10
2024
medline:
23
10
2023
pubmed:
6
8
2023
entrez:
5
8
2023
Statut:
ppublish
Résumé
OSCA/TMEM63s form mechanically activated (MA) ion channels in plants and animals, respectively. OSCAs and related TMEM16s and transmembrane channel-like (TMC) proteins form homodimers with two pores. Here, we uncover an unanticipated monomeric configuration of TMEM63 proteins. Structures of TMEM63A and TMEM63B (referred to as TMEM63s) revealed a single highly restricted pore. Functional analyses demonstrated that TMEM63s are bona fide mechanosensitive ion channels, characterized by small conductance and high thresholds. TMEM63s possess evolutionary variations in the intracellular linker IL2, which mediates dimerization in OSCAs. Replacement of OSCA1.2 IL2 with TMEM63A IL2 or mutations to key variable residues resulted in monomeric OSCA1.2 and MA currents with significantly higher thresholds. Structural analyses revealed substantial conformational differences in the mechano-sensing domain IL2 and gating helix TM6 between TMEM63s and OSCA1.2. Our studies reveal that mechanosensitivity in OSCA/TMEM63 channels is affected by oligomerization and suggest gating mechanisms that may be shared by OSCA/TMEM63, TMEM16, and TMC channels.
Identifiants
pubmed: 37543036
pii: S0896-6273(23)00512-3
doi: 10.1016/j.neuron.2023.07.006
pmc: PMC10592209
mid: NIHMS1923029
pii:
doi:
Substances chimiques
Interleukin-2
0
Ion Channels
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3195-3210.e7Subventions
Organisme : NIGMS NIH HHS
ID : P41 GM103310
Pays : United States
Organisme : NIDCD NIH HHS
ID : R01 DC013521
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2023 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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